Carlos said it mostly well (except suggestions that I somehow know this
better).

Villin is a relatively challenging "protein" of its size. Helix-one does
not have strong contacts with the rest and is actually perpendicular to
the other two helices. Although I have not tried GB or GB/SA on villin,
I expect this helix to fluctuate, although one should be able to
maintain its helicity reasonably well.

I'd encourage you to look into the cause of the large RMSD. If this was
caused by the movement of helix-one, it probably implies the dynamic
nature of the helix. In which case, although this large RMSD raises a
bit concern, I would not think this constitutes a major problem. If the
overall structure is ok, continuation of the simulation may be
justified.

Other than helix-one, there is a phe residue at the C-terminal which has
the tendency to stick with hydrophobic surface. But for some reason, it
stays in solvent in the NMR structure. There could be several
explainations. An obvious explaination is that it is disordered and
actually assumes several conformations with similar stability. So, this
would explain the NMR data. Another explaination is that the force field
over-estimates the hydrophobic force. If so, correction of this problem
is pretty difficult to develop and a challenge to the community.
However, given the consistent observation in X-ray structures that phe
residue does not like to stay in solvent, which is consistent with a
good number of simulations, I am uncertain how much faith we can put on
such an explaination.

Other than these two possible problems, if you indeed observe
considerable conformational changes on other parts of the peptide, we
would like to know.

Also keep in mind, one typically observes more stable structures in
simulations when they are started from X-ray structures. For some
reason, NMR structures tend to be somewhat less stable which is
counter-intuitive. So, it may be a good idea to be cautious when you
start the simulations. For example, one may consider a relatively long
equilibration process at low temperature. My favorite choose is 1.0ns at
100K and then raise the temperature a bit slowly. In most cases, I'd say
such an elaborate equilibration is unecessary when the simulations are
started from X-ray structures and are in solvated environment. But for
GB or GB/SA simulations, this could be justified. Besides, it never
hurts to be careful.